1. Field of the Invention
The present invention relates generally to the field of medical apparatus and instrumentation and more particularly to the field of non-pharmacologic treatment of cardiac disorders including arrhythmias and ischemias, including percutaneous treatment, with specific application to the ablation or modification of tissues responsible for the arrhythmia, and for protection of ischemia reperfusion injury by application of local hyperthermal treatment.
2. Description of the Related Art
Cardiac arrhythmias arise when the rhythmic electrical signal from the heart""s intrinsic pacemaker is not correctly propagated throughout the heart. A particular type of cardiac arrhythmia is a ventricular tachycardia, in which an ectopic focus occurs in the ventricle of the heart resulting in a heartbeat of over 100 beats per minute. This problem often occurs near a site of damaged myocardial tissue caused by an infarction or other injury.
Heating and thus coagulating (xe2x80x9cablatingxe2x80x9d) myocardial tissues responsible for cardiac arrhythmias has been shown to be of great therapeutic value and is frequently done percutaneously (xe2x80x9ccatheter ablationxe2x80x9d). By far the most common method involves delivering radiofrequency energy (RF) via a catheter with a flexible tip equipped with electrodes for sensing (xe2x80x9cmappingxe2x80x9d) the endocardial electrical activation sequence, and for delivering RF energy or laser energy (see Svenson et al., U.S. Pat. No. 5,172,699). The arrhythmias which respond best to this therapy (with a  greater than 90% cure rate) are supraventricular. This is due (1) to well-defined mapping criteria highly predictive of cure and (2) to the small volume of tissue which, when ablated, prevents recurrent arrhythmia. Thus only few, or sometimes one, relatively superficial but well targeted, RF-induced lesion(s) may be necessary for success.
This same approach has been far less successful in treating the ventricular arrhythmias typically originating from tissues damaged by myocardial infarction. RF catheter ablation can be recommended only as adjunctive (not xe2x80x9cfirst linexe2x80x9d) therapy for these arrhythmias. Reasons for this, again, are (1) mapping criteria which are not as clearly correlated with success as in the case of supraventricular arrhythmias and (2) larger tissue volume responsible for the arrhythmia.
An attempt to address the problem of ventricular arrhythmias is described by Isner and Clarke, U.S. Pat. No. 5,104,393, which discloses a catheter for ablation of cardiac tissue. The instrument tip is held in place in the endocardium by a fixation wire, with the ablation tip held on the endocardial wall, and thus, the tip does not directly reach deep intramyocardial tissue where arrhythmias may arise. Other present methods are similarly inadequate for ablating such deep tissue, precluding percutaneous treatment for many patients.
In recent years there has been significant interest in generating elevated levels of heat shock proteins (HSP""s) in the heart and examining their cardioprotective abilities. These efforts have led to the development of experimental protocols in which different stresses such as hypoxia, mechanical strain, hemodynamic overload and hypothermia have been used to express HSP""s (especially the HSP70 family) and examine the subsequent protection to the heart from ischemia/reperfusion (I/R) injury.
Previous work in various in-vitro and in vivo animal models has shown that hyperthermia-induced expression of HSP""s is accompanied by protection against ischemia/reperfusion (I/R) injury of the heart (Marber et al. 1993; Donnely et al. 1992; Yellon et al. 1992; Walker et al. 1993; Currie et al. 1993). This protection has not only been shown to be related to HSP expression but also directly correlated to the amount of HSP induced before I/R (Hutter et al. 1994). Additionally, expression of HSP""s as a result of heat shock response has been shown to improve functional recovery after ischemia and reperfusion (Currie et al. 1988).
In previous hyperthermia studies HSP expression was achieved by either heating the buffer solutions of in vitro isolated hearts or by subjecting animals to whole body hyperthermia 24 hours before I/R. However, whole body heat stress may exert negative effects on extracardiac cells such as blood cells, as the observed duration of cardioprotection in animals treated with whole body hyperthermia in vivo is less than cardioprotection of hearts heat shocked during isolated buffer perfusion in vitro. Walker et al. demonstrated these extracardiac effects in experiments in which buffer perfused hearts and blood (non-heat shock) perfused hearts of animals subjected to whole body hyperthermia were able to withstand longer periods of ischemia than animals subjected to whole body hyperthermia whose hearts were still perfused by the heat shocked blood components.
Their is a need therefore for a method of directly heating the heart and inducing regional HSP expression, thus avoiding limitations that may be induced during whole body hyperthermia.
The present invention addresses the problems described above by (1) delivering laser light or other ablating energy intramyocardially, and (2) diffusing the ablating energy over a broad area in the myocardium without causing excess heat on the endocardial surface or in the blood pool. Mapping of the site of the arrhythmia is made possible by electrodes provided on the catheter sheath that may be switchably connected to a physiological recorder. In a particular embodiment, mapping electrodes may be provided on the retractable tip, in order to more precisely define the area of myocardium in which the arrhythmia arises. The catheter is controllably flexible for placing the electrodes in the correct position for contacting and treating the desired area.
The present invention thus provides instruments and methods for percutaneous catheter ablation of larger myocardial lesions than have previously been possible, by the intramyocardial delivery of diffused laser light, or other ablating energy, thus enhancing the potential for cure of ventricular arrhythmias, for example. Patients may therefore not require pharmacological or surgical therapy, reducing the morbidity and expense of therapy.
The invention, in certain aspects, may be described as an apparatus for endocardial insertion comprising a catheter adapted to access the cardiovascular system. An energy transmitting conductor extends along and within the catheter and has a tip which is extensible beyond the distal end of the catheter and also retractable within the catheter. The conductor may be a conductor for electrical current, ultrasound, microwave, an optical wave guide such as a wave guide for coherent light or a conduit for liquid and most preferably comprises an optical fiber.
The tip of the conductor is configured to penetrate cardiac tissue (i.e. through the endocardium and into the myocardial tissue) and to direct energy from and radially and/or axially relative to the conductor when the conductor is extended beyond the distal end of the catheter and into the myocardial tissue. The tip may form a pointed end, in order to more easily penetrate the endocardium, or the tip may form a flat end, a flat elliptical end or other appropriate configuration. Exemplary tips are described in U.S. Pat. No. 5,253,312, or U.S. Pat. No. 5,269,777 incorporated herein by reference. A preferred tip is the diffusing laser tip available from Rare Earth Medical Lasers Inc., Dennis, Mass. The end of the tip may also be coated or coupled with an energy or light reflecting or deflecting material in order to prevent forward propagation of the ablating energy. This feature increases the safety of the present invention by helping to prevent unwanted perforation of cardiac tissue.
The apparatus may also have one or more electrodes positioned near the distal end of the catheter and may preferably have an electrode pair positioned at the distal end of the catheter to be used to accurately map the arrhythmia. Alternatively, the apparatus may even provide one or more electrodes positioned on the retractable tip for interstitial mapping. Additional electrodes may be positioned on a probe that may be advanced from the end of the catheter into the tissue for recording intramyocardial electrical activity. It is understood that the conductor for the mapping electrodes is preferably incorporated into the sheath of the catheter. However, in those embodiments in which a mapping probe is extensible beyond the catheter sheath, a conductor may pass through the lumen of the catheter in addition to the conductor of ablating energy. Apparatus and methods for stimulating, pacing, and endocardial mapping of arrhythmias are well known in the art, and they are not, in and of themselves, considered to constitute the present invention. The overall apparatus will preferably include a physiological recorder switchably connected to at least one of the electrodes operable to map local cardiac electrical activity and may further comprise an electrical stimulating device switchably connected to at least one of the electrodes operable to pace or otherwise stimulate the heart tissue. The pacing electrodes may be used to induce or to terminate arrhythmias during the procedure. The apparatus may further comprise a stabilizer, or stabilizing device to help prevent unwanted penetration of heart tissue. The stabilizer is exemplified by, but is not limited to, an inflatable, doughnut-shaped balloon that expands radially and may expand distally relative to the catheter. The stabilizer may be positioned on the outer surface of the catheter to stabilize the catheter within a body organ or cavity. Other stabilizers may include, but are not limited to disk or basket shaped extensions which are attached to the catheter""s distal tip.
The present invention may also be described as a maneuverable catheter for ablation of cardiac tissue. where the catheter has a retractable tip, and the tip is extendible into the myocardium tissue for lateral diffusion of ablating energy into the intramyocardial tissue. The ablating energy may be provided in the form of laser energy, radiofrequency energy, microwave, ultrasound or a medium such as hot water, and is preferably 400 to 3,000 nm wavelength laser energy.
A certain aspect of the present invention resides in a method of treating cardiac arrhythmia which comprises the steps of positioning the distal end of an apparatus as described above on the endocardium, identifying the tissue involved in the arrhythmia, extending the distal end of the conductor past the distal end of the catheter and into the tissue. and transmitting ablating energy through the conductor into the tissue. In the practice of this method. the conductor may be a waveguide and the ablating energy may be laser energy. The distal end of the waveguide preferably comprises a penetrating tip and means for distributing laser energy into the selected tissue in a desired pattern, which may be a uniform distribution extending radially from the waveguide.
In certain embodiments, the present invention may be described as a method for promoting myocardial revascularization, through a process called angiogenesis. In the preferred method of practicing this embodiment, the tissues are heated to about 40xc2x0 C. by introducing the catheter tip into the myocardium which has been previously identified as being underperfused with blood (i.e., ischemic). The procedure would be performed in a manner similar to that described for the treatment of arrhythmias, except in most cases it would be performed intraoperatively and involve a larger volume of tissue.
As shown herein, the protective effect of local hyperthermia may be due to the induction of heat shock proteins. Since heat shock proteins (HSP) are a non-specific response to injury, it is contemplated that other mechanical, thermal, optical, electrical and photochemical means may be used to induce HSP locally in the heart. Therefore any device that may deliver any of such types of energy to the area of the heart may be used to induce local injury in the heart tissue thus elevating HSP and other substances that could have protective effects. However, it is contemplated that local irradiation and/or heating may provide a the safest and most preferred approach to local elevation of HSP in the heart. Local temperature elevation in myocardial tissue can be realized by heating from the epicardial surface, endocardial surface, interstitial heating or a combination of these modalities.
In the practice of the method, devices emitting laser, ultrasound, microwave, radiofrequency or conductive heat as from a hot tip may be used to heat the heart tissue. These devices may, by way of example only, be placed in a blood vessel, they may be introduced through a natural opening such as an esophagus to irradiate and/or heat the heart via radiative or conductive heating with or without simultaneous cooling or by opening a small port between the ribs and performing thorocoscopy for treatment of patients with chronic ischemic heart, for example. Such treatment may be administered as a single application, or every 2 to 3 days for a period of time necessary to have a beneficial effect as determined by the practitioner. Such treatments may be administered for protection of transplant, bypass or other patients, including for example patients receiving transplanted organs other than a heart such as a kidney, for example.
The present invention may then be described in certain embodiments as an apparatus for inducing hyperthermic, coagualative or photochemical processes in cardiac tissue. The apparatus would include a catheter adapted to access the cardiovascular system and a conductor extending along and within the lumen of the catheter for transmitting energy to the distal end of the catheter. The conductor preferably has a distal end which is extensible beyond the distal end of the catheter and there is also included an energy source in communication with the proximal end of the conductor effective to transmit energy through the conductor and into a tissue in contact with the conductor to increase the temperature of the tissue above 37xc2x0 C. in order to modulate biological responses and promote tissue angiogensis and/or tissue protection. As is well known in the art, such a method is a time and temperature dependent process so that more or less energy may be applied over a longer or shorter period of time to achieve the same effect. However, any such use of an instrument to increase the temperature to a level that will induce endogenous protective mechanisms such as heat shock proteins or growth factors is encompassed by the spirit and scope of the present claimed invention. Preferred energy sources for the practice of this embodiment include, but are not limited to light, microwave, heated liquid, ultrasound, radiofrequency, or direct current energy, and the light energy may be laser, ultraviolet, visible or infrared light energy.
The present invention may also be described in certain embodiments as a method of inhibiting tissue damage due to insults such as reperfusion injury comprising providing radiative or conductive energy to said tissue in an amount effective to induce local hyperthermia and facilitate endogenous expression of heat shock protein and growth factors. This method may be used in cardiac tissue or heart tissue through application of energy endocardial surface, the epicardial surface or interstitial area of the heart. The method may also be applied to other organs, particularly organs to be transplanted. This method would include heating the organ in vivo or in vitro for a desired time at sublethal temperature via heat conduction from the surface of the organ, or directly within the organ by using various sources of energy such as laser, ultrasound, microwave, electrical current or radiofrequency to stimulate the endogenous expression of proteins and structures such as heat shock proteins that are capable of providing additional means to protect the tissue and thus extend the time for tissue transplant and/or improve the outcome of organ transplant.
The invention may also be described in certain embodiments as a method of delivering light and/or heat to tissue in order to manipulate and/or modulate biological response and stimulate the endogenous expression and release of substances such as heat shock proteins and growth factors such as vascular endothelial growth factor (VEGF), for example. For example, a device that is used to deliver light superfically and/or interstitially for photodynamic processes that will lead to the induction of angiogensis or tissue protection in cardiac tissue with or without the use of an exogenous light activated substance that may facilitate the expression of such substances in cardiac tissue.
An embodiment of the present invention is also the use of interstitial illumination in combination with light activated substances that may induce heat shock protein and/or promote the growth factors. Optical and ultrasound energy may be introduced to activate exogenous substances that have been administered such as those known in the art to be effective in photodynamic therapy. It Is contemplated that such use may induce a protective response in myocardial tissue as described herein.
As used herein, xe2x80x9cablatexe2x80x9d means to thermally coagulate and/or remove the tissues where arrhythmias originate or through which arrhythmias are sustained, and in a more general sense, ablation means the desiccation of tissue by the application of heat. For example, an ablating energy would be one that would cause the tissue to reach a temperature of at least about 80-90xc2x0 C. Hyperthermia is defined as a temperature above normal body temperature (37xc2x0 C.), but usually less than the temperature necessary to cause tissue coagulation. Alternatively ablation may be achieved by selectively targeting cell surface proteins or gene loci for deactivation to affect electrical conduction without desiccating the target tissue. For example, ion channels responsible for cellular action potentials (e.g., potassium and sodium channels) and for intercellular communication (the conexins) may be influenced. Photodynamic therapy (PDT) with light activated substances (e.g. tagged antibodies or DNA) may be a preferred method for this type of ablation. Additionally, the tissue substrate for arrhythmia development may be favorably altered by reducing the development of myocyte hypertrophy and intercellular collagen, features of infarct healing and myocardial remodeling that induce myocardial dysfunction and increase the likelihood of life-threatening ventricular arrhythmias. It is contemplated that the present device may influence the degree of local hypertrophy and collagen formation (or collagen breakdown) by directly changing relevant proteins or their genetic expression. Finally, this device may be used to induced apoptosis in regions of local myocyte hypertrophy, such as occurs in the septum of patients with hypertrophic obstructive cardiomyopathy.